Targeted cancer immunotherapy, as compared to chemotherapy, holds the promise of not only better efficacy, both short-term and long-term, but also fewer side effects.
For example, anti-cancer vaccines targeting a tumor-specific carbohydrate antigen, e.g., Globo H, stage-specific embryonic antigen 3 (“SSEA3”), and stage-specific embryonic antigen 4 (“SSEA4”) have been developed to stimulate a patient's own immune system to develop antibodies against these antigens, which leads to antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis, complement-dependent cell lysis, as well as direct cytostatic and/or cytotoxic effects.
Such an approach often loses effectiveness over time as a result of an inhibitory environment in the tumor. The inhibitory environment blocks one or all of antibodies, NK cells, macrophages, and complement from entering the tumor.
Recently, chimeric antigen receptors (“CARs”) have been developed to obviate the drawbacks mentioned above. A CAR contains (i) an extracellular domain that binds to the tumor antigen and (ii) one or more intracellular domains that provide both primary and co-stimulatory signals to the T cells. T cells can be engineered in vitro to express CAR having an extracellular domain of choice.
The CAR approach has proven to be effective, yet not without serious side effects. For example, activation of a large number of T cells expressing CAR causes cytokine release syndrome. This syndrome, characterized by high fever, hypotension, and hypoxia, can result in multi-organ failure and even death.
There is a need to develop CAR-based tumor therapies that are safer and more effective than those currently in use.